Synthesis of 4/5-pyrimidinylimidazoles via sequential functionalization of 2,4-dichloropyrimidine

ABSTRACT

This invention relates to methods of making pyrimidinyl-substituted imidazole compounds by sequential substitution of the 4- and 2-chloro groups of 2,4-dichloropyrimidine, nucleophilic substitution to form pyrimidinylalkyne derivatives, oxidation to the corresponding 1,2-diketones, and cyclocondensation reactions.

This application is a divisional of U.S. patent application Ser. No.11/494,060, filed on Jul. 27, 2006, which in turn claims the benefit ofU.S. Provisional Patent Application No. 60/703,078, filed Jul. 28, 2005,and 60/726,690, filed Oct. 14, 2005, each of which is incorporatedherein by reference in its entirety.

FIELD OF THE INVENTION

This invention relates to methods of making pyrimidinyl-substitutedimidazole compounds. More particularly, this invention relates tomethods of oxidizing pyrimidinyl alkynes to pyrimidinyl diketones, whichare useful in the preparation of pyrimidinyl-substituted imidazolecompounds.

BACKGROUND OF THE INVENTION

4,5-Diaryl-imidazoles, in which one of the aryl substituents is aheteroaryl group such as a pyridine or pyrimidine, form an importantclass of p38 MAPK (mitogen-activated protein kinase) inhibitors,reportedly pursued by a number of pharmaceutical companies asanti-inflammatory drugs (Fullerton, T. et al. Clin. Pharmacol. Ther.2000, 67, 114). Examples of such pyrimidinyl imidazoles include:

Additional examples of such compounds include inhibitors of proteintyrosine kinases such as: c-Met tyrosine kinase and src kinase (See:U.S. Pat. Appl. Publ. 2005085473; Intl. Pat. Appl. Publ. WO03/087026)for the treatment of, for example, transplant rejection, inflammatorybowel syndrome, rheumatoid arthritis, psoriasis, restenosis, allergicasthma, Alzheimer's disease, Parkinson's disease, stroke, osteoporosis,cancer, and benign hyperplasia; and inhibitors of p38 MAP kinase asanti-cancer (Intl. Pat. Appl. Publ. WO03/087026) and anti-inflammatoryagents (Revesz, L. et al. Bioorg. Med. Chem. Lett. 2004, 14(13),3595-3599); inhibitors of B-raf kinase (Intl. Pat. Appl. Publ.WO01/038324) for the treatment of cancer and neuronal degeneration fromischemic events.

In spite of the heightened interest, preparation of these compounds hasrelied largely upon two synthetic strategies. Reported methodologies(Liverton, N. J. et al. J. Med. Chem. 1999, 42, 2180-2190; McIntyre, C.J. et al. Bioorg. Med. Chem. Lett. 2002, 12, 689-692) employed thecyclocondensation of substituted 1,2-dicarbonyl compounds with ammoniaand an aldehyde. Although this reaction is quite efficient, preparationof the pyrimidinyl-substituted dicarbonyl derivatives reportedlyproceeds through a lengthy sequence starting from2-mercapto-4-methylpiperidine. Another approach (Adams, J. L. et al.Bioorg. Med. Chem. Lett. 2001, 11, 2867-2870, and literature citedtherein) involved the cycloaddition of substituted TosMIC withaldimines, originally pioneered by van Leusen (Van Leusen, A. M. et al.J. Org. Chem. 1977, 42, 1153-1159). More recently, Merck scientists havereported a promising one-pot synthesis of imidazoles based on thecyclocondensation of an α-ketoamide with an amine, wherein the requisiteα-ketoamide was generated in situ by a Stetter reaction involving anα-amidosulfone (Frantz, D. E. et al. Org. Lett. 2004, 6, 843-846). Inthese cases also, access to the suitably elaborated pyrimidines requiredmulti-step sequences.

To successfully exploit the particularly efficient condensation of1,2-diketones bearing an electron-deficient pyrimidine moiety with analdehyde and ammonia, a more succinct route to the requisite1,2-diketone derivatives would clearly be advantageous.

To more readily access the desired 1,2-diketone intermediates, weconsidered the oxidation of disubstituted acetylene compounds, whichcould be derived from the readily available 2,4-dichloropyrimidinethrough sequential substitution reactions (Scheme 1). Cyclocondensationof the resulting diketones of Formula (I) would provide the desiredpyrimidinyl imidazoles. 1,2-Diketones of Formula (I) are useful in thepreparation of pharmaceutically active pyrimidinyl imidazole compounds.

SUMMARY OF THE INVENTION

Relative to existing methods, embodiments of the synthetic routeaccording to this invention provide a concise methodology that issuitable for readily making a range of structurally related 1,2-diketoneand imidazole analogs.

There are provided by the present invention methods of making aminosubstituted 1-(pyrimidin-4-yl)-2-phenyl-ethane-1,2-diones of Formula(I):

wherein:

-   -   R¹ and R² are each independently selected from the group        consisting of —H, —C₁₋₆alkyl, —C₃₋₈cycloalkyl, benzyl, and        1-methylbenzyl;    -   x is 0, 1, 2, or 3; and    -   each R³ is independently selected from the group consisting of        —OH, —Cl, —F, —C₁₋₆alkyl, —C₃₋₈cycloalkyl, —OC₁₋₆alkyl, —CF₃,        —OCF₃, phenyl, —CN, —NO₂, —N(R^(a))R^(b), —C(O)N(R^(a))R^(b),        —N(R^(c))C(O)R^(d), —N(R^(c))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,        —S(O)₀₋₂C₁₋₆alkyl, —SO₂N(R^(a))R^(b), —CO₂H, and —CO₂C₁₋₆alkyl,        where R^(a) and R^(b) are each independently —H or —C₁₋₆alkyl,        and where R^(c) and R^(d) are each independently —H or        —C₁₋₆alkyl;    -   and enantiomers, diastereomers, and pharmaceutically acceptable        salts and esters thereof;    -   comprising oxidizing an alkyne of Formula (II):

wherein R¹, R², R³, and x are defined as above,

with finely powdered potassium permanganate.

The present invention further contemplates methods of making imidazolesof Formula (III):

and tautomers thereof, wherein R¹, R², R³, and x are defined as above;and

-   -   R⁴ is —H, —C₁₋₈alkyl, —C₃₋₈cycloalkyl, aryl, heteroaryl,        heterocycloalkyl, or —CH(OC₁₋₆alkyl)₂;

comprising oxidizing an alkyne of Formula (II) to a 1,2-diketone ofFormula (I) with finely powdered potassium permanganate. Reactions suchas the oxidation of an alkyne of Formula (II) are performed in someembodiments of this invention in a buffered solution of suitablepolarity that is chemically compatible with the reaction conditions.

The present invention further contemplates methods of making4/5-pyrimidinylimidazoles comprising reacting 2,4-dichloropyrimidinewith a nucleophilic-attack-protected-acetylene to form2-chloro-4-(protected-ethynyl)pyrimidine.

The present invention further contemplates methods of making4/5-pyrimidinylimidazoles comprising reacting 2,4-dichloropyrimidinewith a compound of Formula (VII):

to form a compound of Formula (VIII):

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

DETAILED DESCRIPTION OF THE INVENTION

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications cited in this specification are herein incorporated byreference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by /), ethyl(Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu),pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, and groups that inlight of the ordinary skill in the art and the teachings provided hereinwould be considered equivalent to any one of the foregoing examples.

The term “alkylene” refers to a divalent straight- or branched-chainalkyl group having from 1 to 12 carbon atoms in the chain. Examples ofalkylene groups include methylene, ethylene, propylene, and groups thatin light of the ordinary skill in the art and the teachings providedherein would be considered equivalent to any one of the foregoingexamples.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 12 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two sp² hybridized carbon atoms.)Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, and groups that in light of theordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples.

The term “alkynyl” refers to a straight- or branched-chain alkynyl grouphaving from 2 to 12 carbon atoms in the chain. (The triple bond of thealkynyl group is formed by two sp hybridized carbon atoms.) Illustrativealkynyl groups include prop-2-ynyl, but-2-ynyl, but-3-ynyl,2-methylbut-2-ynyl, hex-2-ynyl, and groups that in light of the ordinaryskill in the art and the teachings provided herein would be consideredequivalent to any one of the foregoing examples.

The term “aryl” refers to a monocyclic or fused polycyclic, aromaticcarbocycle (ring structure having ring atoms that are all carbon) havingfrom 3 to 12 ring atoms per carbocycle. (Carbon atoms in aryl groups aresp² hybridized.) Illustrative examples of aryl groups include phenyl,naphthalenyl, anthracenyl, phenanthrenyl, and groups that in light ofthe ordinary skill in the art and the teachings provided herein would beconsidered equivalent to any one of the foregoing examples.

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic, aromatic heterocycle (ring structure having ring atomsselected from carbon atoms as well as nitrogen, oxygen, and sulfurheteroatoms) having from 3 to 12 ring atoms per heterocycle.Illustrative examples of heteroaryl groups include the followingentities, in the form of properly bonded moieties:

and moieties that in light of the ordinary skill in the art and theteachings provided herein would be considered equivalent to any one ofthe foregoing examples.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic or fused or spiro polycyclic, carbocycle having from 3 to 12ring atoms per carbocycle. Illustrative examples of cycloalkyl groupsinclude the following entities, in the form of properly bonded moieties:

and moieties that in light of the ordinary skill in the art and theteachings provided herein would be considered equivalent to any one ofthe foregoing examples.

A “heterocycloalkyl” refers to a monocyclic, or fused or spiropolycyclic, ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from C atoms andN, O, and S heteroatoms. Illustrative examples of heterocycloalkylgroups include the following entities, in the form of properly bondedmoieties:

and moieties that in light of the ordinary skill in the art and theteachings provided herein would be considered equivalent to any one ofthe foregoing examples.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at any valenceallowed position on the system. It is understood that substitutions andcombinations of substitutions recited herein, whether stated explicitlyor not, refer to substitutions that are consistent with the valence ofthe member being substituted. Terms such as “valence allowed”, “valenceallowed site”, “valence allowed member” and morphological variationsthereof are used herein in this sense. For example, “valence allowed”when applied to a carbon member refers to the tetravalency of C; itrefers to the trivalency of N when applied to a nitrogen member; and itrefers to the bonding of a nitrogen member that is conventionallycharacterized with a positive electric charge or that is in a quaternaryform. The present invention also encompasses compounds as describedherein and equivalents thereof with at least one valence allowednitrogen member, including but not limited to a quaternary nitrogenmember and a nitrogen oxide. Such quaternary nitrogen member can begenerated with a known agent for this purpose, such as lower alkylhalides, dialkyl sulfates, long chain halides, and aralkyl halides.Valence allowed options are part of the ordinary skill in the art.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any given formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus any given formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof.

Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers. Additionally,any formula given herein is intended to represent hydrates, solvates,and polymorphs, and mixtures thereof when such forms exist in themedium.

The term “4/5-pyrimidinylimidazole” as used herein refers to animidazole ring where the pyrimidinyl subsittuent is in the 4- or the5-position in the imidazole ring, and it also refers to the pair ofpyrimidinyl imidazole tautomers. It is known that subsituted imidazolescan interconvert due to tautomerism, and that one tautomeric form (forexample the 4-substituted) may appear as the predominant form in acertain medium whereas the other tautomeric form (for example the5-subsituted) may appear as the predominant form in a different medium.It is understood that, unless specified otherwise, reference to asubstituted imidazole, whether referred to as 4/5 substituted imidazoleor not, refers to and encompasses whichever tautomeric form is presentin the medium, and if both tautomers are present in such medium, then itrefers to and encompasses both tautomers. This lexicography also appliesto the chemical structures given herein. Accordingly, a chemicalstructure that displays the imidazole moiety given as

or as

refers to any one of the tautomers or to the tautomer pair, depending onwhether one tautomer, the other tautomer or the pair is present in themedium. (R^(α), R^(β), and R^(γ) in these tautomeric structures aregeneric substituents that refer to any one of the imidazolesubstituents/moieties referred to herein).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine,chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵ _(N,) ¹⁸O, ¹⁷O,³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I, respectively. Such isotopicallylabelled compounds are useful in metabolic studies (preferably with¹⁴C), reaction kinetic studies (with, for example ²H or ³H), detectionor imaging techniques [such as positron emission tomography (PET) orsingle-photon emission computed tomography (SPECT)] including drug orsubstrate tissue distribution assays, or in radioactive treatment ofpatients. In particular, an ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET or SPECT studies. Further, substitutionwith heavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.Isotopically labeled compounds of this invention and prodrugs thereofcan generally be prepared by carrying out the procedures disclosed inthe schemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the moiety for the variable appearingelsewhere. In other words, where a variable appears more than once, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula, unlessstated otherwise.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻⁴, R^(1′-4′) and x, and any other generic substituent symbol usedherein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such asR¹⁻⁴, R^(1′-4′) and x, and any other generic substituent symbol usedherein.

The nomenclature “C_(1-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

“Finely powdered” potassium permanganate refers to this compound in aform that is recognized in the manufacturing and marketing of thiscompound with this characterization. An example of finely powderedpotassium permanganate is the product Cairox M®, marketed by CarusChemical Company. Embodiments of finely powdered potassium permanganateinclude forms of this compound that have a particle size of at least 325mesh. In one illustrative embodiment, finely powdered potassiumpermanganate is provided in samples that completely pass through #325standard sieve (44 micron). Preferably, potassium permanganate is of atleast 98% purity.

The terms “buffered” solution or “buffer” solution are used hereininterchangeably according to their standard meaning. Buffered solutionsare used to control the pH of a medium, and their choice, use, andfunction is known to those of ordinary skill in the art. See, forexample, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry,p. 261, 5^(th) ed. (2005), describing, inter alia, buffer solutions andhow the concentrations of the buffer constituents relate to the pH ofthe buffer. See also Handbook of Chemistry and Physics, 84^(th) ed., pp.8-37 to 8-44. For example, a buffered solution is obtained by addingMgSO₄ and NaHCO₃ to a solution in a 10:1 w/w ratio to maintain the pH ofthe solution at about 7.5.

Solutions used in embodiments of this invention are exemplified by thosethat have one or more miscible solvents that are chemically compatiblewith the reaction conditions, preferably unreactive with permanganate,and that provide a medium that has a dielectric constant comparable withthat of the examples given herein. For example, acetone/H₂O solutionsprovide examples of embodiments of solution media in embodiments of thisinvention. Acetone is a convenient and readily available solvent thatdoes not interfere with the reaction conditions, and is miscible withwater in the proportions desired to achieve a suitable medium polarityfor embodiments of this invention. Dielectric constants for solvents andother liquids are readily available from standard reference materials,such as the Handbook of Chemistry and Physics. One of ordinary skill inthe art should be able to replace acetone/water mixtures with othermixtures based on the teachings provided herein and available referencematerials.

Embodiments of acetone/water solutions include any mixture thereof.Preferably, an acetone/H₂O solution is obtained by mixing acetone andwater in a volume ratio of from about 3:1 to about 5:6, more preferablyfrom about 8:3 to about 6:5, and more preferably about 1.75:1. Othersolvents can be used instead of acetone in other embodiments of thisinvention, and other solvents can be used together with acetone andwater in still other embodiments of this invention, provided that suchmedia have the suitable polarity and chemical compatibility propertiesunder the reaction conditions, as such properties are exemplified hereinand equivalents thereof.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((sol)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent, such as water; and R—COO⁻ _((sol)) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO⁻ upon dissociation in the medium being considered. Inanother example, expressions such as “exposing an entity to compound offormula R—COOH”, “reacting an entity with R—COOH”, and analogousexpressions refer to the exposure of such entity to the form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch exposure and/or reaction takes place. In this regard, if suchentity is for example in an aqueous environment, it is understood thatthe compound R—COOH is in such same medium, and therefore the entity isbeing exposed to species such as R—COOH_((aq)) and/or R—COO⁻ _((aq)),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, ammonia andammonium compounds, and any other group that interacts or transformsaccording to known manners in the medium that contains the compound.Such interactions and transformations include, but are not limited to,dissociation, association, tautomerism, solvolysis, includinghydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

To obtain the various compounds described herein and equivalentsthereof, starting materials may be employed that carry the ultimatelydesired substituents through the reaction scheme with or withoutprotection as appropriate. Alternatively, it may be necessary to employ,in the place of the ultimately desired substituent, a suitable groupthat may be carried through the reaction scheme and replaced asappropriate with the desired substituent.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. Inaddition, compounds of the invention may be modified by using protectinggroups; such compounds, precursors, or prodrugs are also within thescope of the invention. This may be achieved by means of conventionalprotecting groups, such as those described in “Protective Groups inOrganic Chemistry”, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, “Protective Groups in Organic Synthesis”, 3^(rd)ed., John Wiley & Sons, 1999; further examples of protecting groups arewell known in organic synthesis and the peptide art, and are describedby M. Bodanzsky, Principles of Peptide Synthesis, 1st and 2nd reviseded., Springer-Verlag, New York, 1984 and 1993; Stewart and Young, SolidPhase Peptide Synthesis, 2nd ed., Pierce Chemical Co, Rockford, Ill.1984; L. Fieser and M. Fieser, Fieser and Fieser's Reagents for OrganicSynthesis, John Wiley and Sons (1994); L. Paquette, ed., Encyclopedia ofReagents for Organic Synthesis, John Wiley and Sons (1995). Aminoprotecting groups are also given in, e.g., WO 98/07685. The protectinggroups may be removed at a convenient subsequent stage by using methodsknown from the art. One or more than one protecting groups may often beused in a protection/deprotection operation. The choice typicallyintends to provide a protected group that will be stable under theconditions of subsequent reactions, and that can be removed at anappropriate step without disrupting the rest of the compound.

The methods of making imidazoles of Formula (III) may further comprisereacting, in the presence of an ammonia equivalent, a 1,2-diketone ofFormula (I) with R⁴CHO, where R⁴ is defined as above, or with aformaldehyde equivalent.

Suitable formaldehyde equivalents include hexamethylenetetramine,formaldehyde, and the like, and mixtures thereof. Suitable ammoniaequivalents include ammonia, ammonium salts such as ammonium acetate andthe like, and mixtures thereof.

The present invention further contemplates methods of making compoundsof Formula (I), comprising at least one of:

-   a) reacting 2,4-dichloropyrimidine with (trimethylsilyl)acetylene to    form 2-chloro-4-trimethylsilanylethynyl-pyrimidine;-   b) reacting 2-chloro-4-trimethylsilanylethynyl-pyrimidine with    R¹R²NH to form a (trimethylsilyl)alkyne of Formula (IV):

-   c) deprotecting a (trimethylsilyl)alkyne of Formula (IV) to form an    alkyne of

Formula (V):

and

-   d) reacting an alkyne of Formula (V) with a compound of Formula    (VI):

to form a compound of Formula (II);

wherein R¹, R², R³, and x are defined as above; and

HAL is I or Br.

The present invention further contemplates methods of making compoundsof Formula (I), comprising at least one of:

-   a) reacting 2,4-dichloropyrimidine with a compound of Formula (VII):

to form a compound of Formula (VIII):

and

-   b) reacting a compound of Formula (VIII) with R¹R²NH to form a    compound of Formula (II), wherein R¹, R², R³, and x are defined as    above.

In more particular embodiments, the retrosynthetic scheme may berepresented by Scheme 2.

The preparation of the 1,2-diarylalkynes is described in Schemes 3-5.

Initial attempts to perform selective substitution, outlined in Scheme3, did not produce encouraging results. Reacting 2,4-dichloropyrimidinewith t-butyl amine at 60° C. gave a mixture of 4- and 2-substitutionproducts in 65% and 26% yield respectively. This result clearlyindicated that the chloro group at the 4-position is more reactive(albeit slightly) toward substitution with amine nucleophiles than the2-position (Mylari, B. L. et al. J. Med. Chem. 2001, 44, 2695-2700;Yoshida, K.; Taguchi, M. J. Chem. Soc., Perkin Trans. 1 1992, 7, 919-22;Chu-Moyer, M. Y. et al. J. Med. Chem. 2002, 45, 511-528). Although avariety of base and solvent combinations were investigated, nosynthetically useful 2-position selectivity was found. On smaller scale(5-10 g), the two regioisomers can be separated by columnchromatography. The 4-chloro regioisomer can then be reacted with4-fluorophenylacetylene, under standard Sonogashira coupling conditions(Sonogashira, K. et al. Tetrahedron Lett. 1975, 50, 4467-4470), tofurnish the desired disubstituted acetylene 7a in 76% yield. Although weobtained diarylacetylene 7a in two steps, the poor regioselectivity inthe nucleophilic substitution reaction rendered this approachimpractical for large-scale synthesis.

By reversing the order of the substitution steps, we overcame theregioselectivity issues. We found that a Sonogashira reaction between2,4-dichloropyrimidine and 1-ethynyl-4-fluorobenzene smoothly affordedthe desired regioisomer 8 as the major product (Scheme 4).Unfortunately, nucleophilic substitution of the 2-chloro substituentwith tert-butylamine gave a mixture of the desired compound 7a, alongwith alkyne adduct 9. The structure of 9 was ascertained by nuclearOverhauser effect (NOE) experiments. To avoid this hydroaminationreaction, a variety of conditions, such as Na₂CO₃/EtOH, Et₃N/THF,NH₂Bu^(t)/THF, and Buchwald amination, were investigated without muchsuccess. However, where amines other than tert-butylamine are used inthis transformation, e.g. isopropylamine, yields and regioselectivityare much improved. Reactions using embodiments of amines R¹R²NH that arenot tert-butylamine may be preferably accomplished using R¹R²NH as thesolvent, or in a solvent such as THF or DMF, at temperatures betweenroom temperature and 80° C.

As shown in Scheme 5, a new route was designed: Sonogashiracross-coupling reaction of a nucleophilic-attack-protected acetylene,such as [(tri-4alkyl)silyl]acetylene, for example(trimethylsilyl)acetylene, with 2,4-dichloropyrimidine gave goodregioselectivity in excellent yield. Yields of about 87% were achievedin embodiments of this invention. Heating in neat t-butylamine at 80° C.gave the desired substitution product. It is understood that the SiMe₃protection group in Scheme 5 is replaced in other embodiments of thisinvention by any other protection group that provides similar protectiveeffects to a nucleophilic attack to the alkyne moiety. Such protectivegroups are referred to herein as “nucleophilic-attack protectors”. Anucleophilic-attack-protected acetylene is an acetylene with one of suchprotective groups attached to one of its ends, and a2-chloro-4-protected-ethynyl-pyrimidine is a compound analogous to 10with a nucleophilic-attack protector attached to the acetylenic moietyinstead of the SiMe₃ given in compound 10. Nucleophilic-attackprotectors for alkyne groups are well known. See for example, Greene andWuts, Protective Groups in Organic Synthesis, 3^(rd) ed., chapter 8,which is incorporated herein by reference. Examples of such protectiongroups are trialkylsilanes, including, but not limited to,(tri-C₁₋₄alkyl)silanes such as SiPG¹PG²PG³, wherein each one of PG¹,PG², and PG³ is chosen independently from the other PG groups from thegroup of C₁₋₄alkyl, wherein “alkyl” refers to a straight- orbranched-chain alkyl that has a number of carbon members ranging fromone to four. Specific examples of alkyne protecting groups are providedby TMS (trimethylsilyl), TES (triethylsilyl), TBDMS(t-butyldimethylsilyl), TDS (thexyldimethylsilyl), DOPS(dimethyl[1,1-dimethyl-3-(tetrahydro-2H-pyran-2-yloxy)propylsilyl), BDMS(biphenyldimethylsilyl), TIPS (triisopropylsilyl),biphenyldiisopropylsilyl), and Me₂C(OH) (2-(2-hydroxypropyl)). Finally,desilylation followed by another Sonogashira cross-coupling with4-fluoro-iodobenzene afforded compound 7a in very good overall yield.This reaction sequence was performed successfully on 20-40 g scalewithout the need for column chromatography. Accessing intermediate 10 astaught herein affords a more efficient route to 7a and also allows for apoint of diversification for the design of new analogues. This is adesirable feature for certain applications, such as medicinal chemistryapplications and the making of libraries of compounds. In contrast,conventional methodologies direct the synthetic focus to the formationof a 1,2-diketone. It is to be noted that accessing intermediate 10 astaught herein provides a step that can be implemented in the synthesisof any 4/5-pyrimidinylimidazole, as long as basic principles of chemicalcompatibility are satisfied. This applicability range is due to the factthat the formation of intermediate 10 as taught herein is independent ofand takes place prior to the formation of the eventual imidazole ring.

The synthetic methodology developed in the context of this invention isnot limited by specific theories for the underlying reaction steps. Itis believed, however, that the making of the triple bond less electrondeficient and more sterically encumbered are contributing factors to theresults obtained in embodiments of this invention, so that thenucleophilic substitution preferentially on the pyrimidine nucleus iseffected.

With a reliable route to di-arylsubstituted acetylenes 7a and 8 in hand,we set out to examine the oxidation reaction. Initially, we focused ourattention on the oxidation of entity 8, for it would allow theintroduction of the amine substituent after imidazole formation.Oxidation of diarylsubstituted acetylene to diketone is well precedentedand wide array of reagent systems have been reported (Holland, S.;Epsztein, R. Bull. Chim. Soc. Fr. 1971, 1694; Walsh, C. J.; Mandal, B.K. J. Org. Chem. 1999, 64, 6102-6105; Yusubov, M. S. et al. Tetrahedron2002, 58, 1607-1610). However, oxidation of a diarylacetylene containinga pyrimidine group proved complex and difficult to achieve, asillustrated by the attempts to oxidize entity 8 by using a battery ofreagent systems, attempts that resulted in no oxidation orover-oxidation (Table 1) despite the experience reported in referenceteachings (Chi, K-W. et al. Synth. Commun. 1994, 24, 2119). In contrast,in the case of entity 7a, oxidation using KMnO₄ or PdCl₂ went smoothlyon small scale (Table 1, entries 3 and 5). The stark reactivitydifference between entities 7a and 8 could be due to the reducedelectron-deficiency of the triple bond in compound 7a.

TABLE 1 Oxidation of compound 7a.

Entry Conditions Results 1 KMnO₄, CH₂Cl₂, H₂O, AcOH, Over-oxidation^(a)Adogen 64, reflux, 3 h¹ 2 KMnO₄, CH₂Cl₂, AcOH, Adogen 64, 30% reflux 1.5h¹ 3 KMnO₄, Acetone, H₂O, MgSO₄, 45% NaHCO₃, rt, 45 min² 4 I₂/DMSO, 150°C., 16 h³ Over-oxidation^(a) 5 PdCl₂/DMSO, 130° C., 4 h⁴ 53% 6 NBS/DMSO,rt, 10 min⁴ Bromination^(b) 7 HBr/DMSO, 130° C., 3 h⁵ Bromination^(b) 8(CF₃COO)₂IPh, DMSO, 130° C., 3 h⁶ No reaction 9 RuCl₃/NaIO₄,H₂O/CH₃CN/CCl₄, reflux, SM and over- 2 h^(7,8) oxidation^(a) 10 OsO₄,Me₃NO, t-BuOH, H₂O, reflux, 5 h^(9,10) No reaction ^(a)4-Fluorobenzoicacid was isolated. ^(b)Based on MS, the product was not isolated.References for Table 1: ¹Lee, D.G.; Chang, V.S. J. Org. Chem. 1979, 44,2726-2730. ²Srinivasan, N.S.; Lee, D.G. J. Org. Chem. 1979, 44, 1574.³Dötz, F.; Brand, J.D.; Ito, S.; Gherghel, L.; Müllen, K. J. Am. Chem.Soc. 2000, 122, 7707-7717; Ito, S.; Wehmeier, M.; Brand, J.D.; Kubel,C.; Epsch, R.; Rabe, J.P.; Mullen, K. Chem.-Eur. J. 2000, 6, 4327-4342.⁴Chi, K-W; Yusubov, M.S.; Filimonov, V.D. Synth. Commun. 1994, 24, 2119.⁵Yusubov, M.S.; Filimonov, V.D.; Vasilyeva, V.P.; Chi, K-W. Synthesis1995, 10, 1234- 1236. ⁶Kita, Y.; Yakura, T.; Terashi, H.; Haruta, J.;Tamura, Y. Chem. Pharm. Bull. 1989, 37, 891-894. ⁷Sharpless, K.B.;Lauer, R.F.; Repic, O.; Teranishi, A.Y.; Williams, D.R. J. Am. Chem.Soc. 1971, 93, 3303; ⁸Pattenden, G.; Tankard, M.; Cherry, P.C.Tetrahedron Lett. 1993, 34, 2677-2680. ⁹Minato, M.; Yamamoto, K.; Tsuji,J. J. Org. Chem. 1990, 55, 766-768. ¹⁰Page, P.C.B.; Rosenthal, S.Tetrahedron Lett. 1986, 27, 1947-1950.

The oxidation procedures using KMnO₄ and PdCl₂ were furtherinvestigated. In contrast with the KMnO₄ oxidation, the PdCl₂/DMSOoxidizing system exhibited drawbacks, requiring high Pd loading (˜10%),prolonged reaction time, and elevated temperatures (130° C.) to achievereasonably good conversion. Lower Pd loading caused incomplete reactionand raising the temperature caused side reactions. A Pd on C/CuCl₂/DMSOsystem produced similar results (Yusubov, M. S. et al. Synthesis 1995,10, 1234-1236). These methods also required column chromatography topurify the final product, making them less well-suited for large-scalepreparations. Although oxidation using KMnO₄ was more promising in termsof clean reaction and easy purification, over oxidation was a majordisadvantage. Preparation of 1,2-diketones by oxidizing alkynes withfinely powdered potassium permanganate has been reported (Srinivasan, N.S. et al. J. Org. Chem. 1979, 44(9), 1574) for a small class of1,2-diketones that are unrelated to the compounds synthesized accordingto the present invention. These reference teachings on the use ofpotassium permanganate do not teach or suggest the selection of theentities to be oxidized according to this invention, and they do notteach or suggest the specific oxidation reactions that will accomplishsuch oxidation with the features of the methodology according to thisinvention. After screening numerous conditions, it was found that thekey to obtaining good yields with the chemical entities of thisinvention was to use finely powdered KMnO₄ and to control the reactiontime while the reaction was proceeding in a buffered solution. In someembodiments the finely powdered KMnO₄ was KMnO₄ (Cairox M®), purchasedfrom Carus Chemical Company. An example of such buffered solution usedin embodiments of this invention is an acetone/H₂O solution bufferedwith MgSO₄ and NaHCO₃. The buffering is preferably performed inembodiments of this invention to control the pH in the range from about7 to about 8. Some embodiments of this invention were performed with theoxidation being performed in a solution buffered at a pH of about 7.5.Under these optimized conditions, the desired diketone 6a was obtainedconsistently in 65-70% yields on 5-g scale after simple aqueous workupand without column chromatography.

Many literature methods have been reported that efficiently oxidizesimple diphenylacetylene compounds. A variety of these methods wereexamined to oxidize pyrimidinyl-substituted acetylene analogs, but werenot successful. Therefore, based on the application of conventionalmethods from the literature and the poor results as applied to compoundsof Formula (I), the success of the finely powdered KMnO₄ procedure wasunexpected.

Reaction control was achieved by monitoring the reaction and quenchingit by the addition of NaHSO₃ when complete.

Using the method described above, iso-propyl analog 6b was also preparedin good yield. Cyclocondensation of the diketones with ammonium acetateand an aldehyde efficiently provided various pyrimidinyl-substitutedimidazoles.

Embodiments of this invention provide a concise, 6-step sequence tosynthesize 4-aryl-5-pyrimidinyl imidazoles—an important scaffold usefulin medicinal chemistry, such as in anticancer, antiviral, andanti-inflammatory medicinal chemistry. The methodology is well-suited tothe preparation of a number of related analogs.

There are provided by the present invention methods of making aminosubstituted 1-(pyrimidin-4-yl)-2-phenyl-ethane-1,2-diones of Formula(I′):

wherein

-   -   R^(2′) is isopropyl or t-butyl;    -   comprising oxidizing an alkyne of Formula (II′):

wherein R^(2′) is defined as above,

-   -   with finely powdered potassium permanganate in a buffered        acetone/H₂O solution.

The present invention further contemplates methods of making imidazolesof Formula (III′):

and tautomers thereof, wherein

-   -   R^(2′) is defined as above; and    -   R^(4′) is —H, 4-chlorophenyl, or —CH(OCH₃)₂;    -   comprising oxidizing an alkyne of Formula (II′) to a        1,2-diketone of Formula (I′) with finely powdered potassium        permanganate in a buffered acetone/H₂O solution.

The present invention further contemplates methods of making compoundsof Formula (I′), comprising at least one of:

-   a) reacting 2,4-dichloropyrimidine with (trimethylsilyl)acetylene to    form 2-chloro-4-trimethylsilanylethynyl-pyrimidine;-   b) reacting 2-chloro-4-trimethylsilanylethynyl-pyrimidine with    R^(2′)NH₂ to form a (trimethylsilyl)alkyne of Formula (IV′):

-   c) deprotecting a (trimethylsilyl)alkyne of Formula (IV′) to form an    alkyne of Formula (V′):

and

-   d) reacting an alkyne of Formula (V′) with 4-iodo-fluorobenzene to    form a compound of Formula (II′);    wherein R^(2′) is defined as above.

The present invention further contemplates methods of making compoundsof Formula (I′), comprising at least one of:

-   a) reacting 2,4-dichloropyrimidine with 1-ethynyl-4-fluorobenzene to    form a compound of formula (VIII′):

and

-   b) reacting a compound of formula (VIII′) with R^(2′)NH to form a    compound of Formula (II′), wherein R^(2′) is defined as above.

Examples

In order to illustrate the invention, the following examples areincluded. These examples do not limit the invention. They are meant tosuggest a method of practicing the invention. Those of ordinary skill inthe art may find other methods of practicing the invention, which areobvious to them in light of the teachings provided herein. However,those methods are deemed to be within the scope of this invention.

Gas chromatograph-mass spectrometry (GC-MS) was performed on ShimazuGC-17A Gas Chromatograph and QP5000 Mass Spectrometer using electrosprayionization (ESI) in either positive or negative modes as indicated.Calculated mass corresponds to the exact mass.

NMR spectra were obtained on an INOVA-400 NMR spectrometer (¹H, 400 MHz;¹³C, 100 MHz) or Bruker 500 NMR spectrometer (¹H, 500 MHz; ¹³C, 125 MHz)as solutions in CDCl₃ and were internally referenced to the solvent (¹H,7.26 ppm; ¹³C, 77.23 ppm). The format of the ¹H NMR data below is:chemical shift in ppm (multiplicity, coupling constant J in Hz,integration).

Infrared (IR) Spectroscopy was performed on a Nicolet 510 FT-IR with aresolution of 4 cm⁻¹ on dry film. IR absorptions are reported in cm⁻¹.Uncalibrated melting points were taken on a Thomas-Hoover melting pointapparatus in open capillary tubes. Elemental analyses were performed byNuMega Resonance Labs, Inc., San Diego, Calif.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄plates, eluting with 20% EtOAc/hexanes unless otherwise specified, andvisualizing with UV, I₂, or phosphomolybdic acid stain. Normal phaseflash column chromatography (FCC) was typically performed using Mercksilica gel 60.

Solvents such as THF, CH₂Cl₂, and CH₃CN were dried over 4 Å molecularsieves. The water level of dried solvents was titrated with a FisherCoulomatic K-F titrator. Other solvents were reagent grade and used asreceived. Unless otherwise specified, all reactions were performed undera nitrogen atmosphere. Unless otherwise specified, reactions wereperformed at room temperature. Solutions were concentrated under reducedpressure on a rotary evaporator.

Example 1 2-Chloro-4-[trimethylsilylethynyl]pyrimidine

To a mixture of Pd(PPh₃)₂Cl₂ (0.9 g) and PPh₃ (0.7 g) in THF (200 mL)and Et₃N (300 mL) was added 2,4-dichloropyrimidine (40 g, 0.27 mol)under a stream of N₂. After bubbling N₂ into the solution for 15 min,Cul (0.5 g) was added, followed by (trimethylsilyl)acetylene (29 g, 0.29mol). The mixture was heated at reflux for 4.5 h. The mixture was cooledto rt and filtered, washing with EtOAc. The filtrated was concentratedand the residue was diluted with hexanes (500 mL) and loaded directlyonto a short pad of SiO₂. The product was eluted with 10% EtOAc/hexanesto provide a light orange solid (49.3 g), which was used without furtherpurification. TLC: R_(f)=0.42. mp 51-54° C. IR: 3125 (w), 2961 (w), 1557(s), 1523 (s). ¹H NMR: 8.58 (d, J=5.0 Hz, 1H), 7.30 (d, J=5.0 Hz, 1H),0.28 (s, 9H). ¹³C NMR: 162.23, 160.16, 153.41, 122.52, 104.23, 100.75,0.01. Anal. Calcd for C₉H₁₁ClN₂Si: C, 51.29; H, 5.26; N, 13.29. Found:C, 51.45; H, 5.16; N, 13.33.

Example 2 2-tert-Butylamino-4-[trimethylsilylethynyl]pyrimidine

A mixture of 2-chloro-4-[trimethylsilylethynyl]pyrimidine (25 g, 0.12mol) and tert-butylamine (100 mL) was heated to 80° C. for 2 d in asealed tube. The mixture was cooled to rt and triturated with hexanes(100 mL). The resulting white precipitate was filtered and washed withhexanes. The filtrate was concentrated to give the crude product as abrown oil, which was used in the following reaction without furtherpurification. TLC: R_(f)=0.40. mp 71-73° C. IR: 3293 (br, w), 2962 (w),1569 (s). ¹H NMR: 8.22 (d, J=5.0 Hz, 1H), 6.57 (d, J=5.0 Hz, 1H), 5.19(s, 1H), 1.42 (s, 9H), 0.26 (s, 9H). ¹³C NMR: 162.38, 158.15, 150.95,112.94, 102.77, 97.62, 51.41, 29.25, -0.11. Anal. Calcd for C₁₃H₂₁N₃Si:C, 63.11; H, 8.56; N, 16.98. Found: C, 63.20; H, 8.52; N, 16.70.

Example 3 tert-Butylamino-4-ethynylpyrimidine

A solution of 2-tert-butylamino-4-[trimethylsilylethynyl]pyrimidine(from Example 2) in CH₃OH (150 mL) was treated with a solution of KOH(30 mg) in CH₃OH (5 mL). After 30 min, additional KOH (30 mg) in CH₃OH(5 mL) was added. After a further 30 min, the mixture was concentratedand the residue was diluted with hexanes and loaded directly onto ashort pad of SiO₂. The product was eluted with 10% EtOAc in hexanes toprovide the crude product as a light brown oil (18.6 g, 90% for 2steps), which was used without further purification. TLC: R_(f)=0.29.IR: 3294 (m), 2965 (m), 2114 (w), 1571 (s). ¹H NMR: 8.23 (d, J=5.0 Hz,1H), 6.60 (d, J=5.0 Hz, 1H), 5.20 (s, 1H), 3.15 (s, 1H), 1.43 (s, 9H).¹³C NMR: 161.97, 157.99, 149.87, 112.63, 81.71, 78.72, 51.06, 28.80.

Example 4 2-tert-Butylamino-4-[4-fluoro-phenylethynyl]pyrimidine

To a mixture of Pd(PPh₃)Cl₂ (0.4 g) in Et₃N (150 mL) and THF (150 mL)under a stream of N₂, was added tert-butylamino-4-ethynylpyrimidine(18.6 g, 0.11 mol). After bubbling N₂ into the solution for 15 min,4-iodo-fluorobenzene (23.6 g, 0.11 mol) and Cul (0.22 g) were addedsequentially. The mixture was stirred at rt for 2.5 h. The precipitatewas filtered and washed with EtOAc. The filtrate was concentrated andthe residue was diluted with EtOAc and loaded directly onto a short padof silica gel. The product was eluted with 10% EtOAc in hexanes toafford the crude product, which was recrystallized from EtOAc/hexanes togive the title compound as a light yellow solid (25 g, 84%). TLC:R_(f)=0.30. mp 97-99° C. IR: 3287 (w), 2964 (w), 2222 (w), 1566 (s). ¹HNMR: 8.26 (d, J=4.2 Hz, 1H), 7.60-7.55 (m, 2H), 7.10-7.00 (m, 2H), 6.65(d, J=4.9 Hz, 1H), 5.22 (s, 1H), 1.45 (s, 9H). ¹³C NMR: 164.19, (162.19,162.03), 157.77, 150.83, (134.35, 134.29), (117.84, 117.81), (115.94,115.76), 112.37, 89.91, 87.24, 51.07, 28.86. Anal. Calcd for C₁₆H₁₆FN₃:C, 71.36; H, 5.99; N, 15.60. Found: C, 71.25; H, 5.95; N, 15.66.

Example 51-(2-tert-Butylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dione

To a solution of 2-tert-butylamino-4-[4-fluoro-phenylethynyl]pyrimidine(5.0 g, 19 mmol) in acetone (225 mL) was added a solution of NaHCO₃(0.40 g) and MgSO₄ (4.0 g) in H₂O (120 mL). Under vigorous stirring,KMnO₄ (Cairox M from Carux Co.; 11.1 g, 70 mmol) was added at rt in oneportion. After 4 min, the reaction was quenched by the addition ofNaHSO₃ (15 g) in H₂O (30 mL). After stirring for 10 min, the mixture wasacidified with 50% H₂SO₄ to pH<2, and extracted with 1:1 Et₂O/hexanes(300 mL) and EtOAc (50 mL). The combined organic layers were washed withaq. K₂CO₃ (1 mol/L, saturated with NaCl; 100 mL) and brine (100 mL),dried (Na₂SO₄), and concentrated to provide the diketone as a lightyellow solid (4.0 g, 71%). TLC: R_(f)=0.15. mp 123-124° C. IR: 3297 (brw), 2968 (w), 1711 (m) 1680 (m), 1596 (s), 1583 (s). ¹H NMR (95%purity): 8.54 (d, J=3.4 Hz, 1H), 8.0-7.90 (m, 2H), 7.22-7.12(m, 3H),5.29 (s, 1H), 1.18 (s, 9H). ¹³C NMR: 195.22, 167.89, 165.33, (161.80,160.37), 157.56, (132.12, 132.02), (129.72, 129.70), (116.45, 116.23),106.42, 51.11, 28.25. Anal. Calcd for C₁₆H₁₆FN₃O₂: C, 63.78; H, 5.35; N,13.95. Found: C, 63.85; H, 5.22; N, 13.94.

Example 6 2-iso-Propylamino-4-[trimethylsilylethynyl]pyrimidine

The title compound was prepared according to the methods described inExample 2, substituting isopropylamine for tert-butylamine. TLC:R_(f)=0.31. mp 93-94° C. IR: 3273 (br w), 2967 (m), 1570 (s). ¹H NMR:8.23 (d, J=5.0 Hz, 1H), 6.59 (d, J=5.0 Hz, 1H), 5.02 (d, J=5.5 Hz, 1H),4.14 (sept, J=6.4 Hz, 1H), 1.21 (d, J=6.4 Hz, 6H), 0.25 (s, 9H). ¹³CNMR: 162.06, 158.68, 151.33, 113.21, 102.70, 98.14, 43.20, 23.28, 0.10.

Example 7 2-iso-Propylamino-4-ethynylpyrimidine

The title compound was prepared according to the methods described inExample 3, substituting2-iso-propylamino-4-[trimethylsilylethynyl]pyrimidine fortert-butylamino-4-ethynylpyrimidine (92% for 2 steps). TLC: R_(f)=0.24.mp 84-85° C. IR: 3256 (br, m), 2974 (w), 2113 (w), 1568 (s). ¹H NMR:8.25 (d, J=5.0 Hz, 1H), 6.62 (d, J=5.0 Hz, 1H), 5.05 (s, 1H), 4.14(sept, J=6.5 Hz, 1H), 3.19 (s, 1H), 1.22 (d, J=6.5 Hz, 6H). ¹³C NMR:162.05, 158.84, 150.66, 113.22, 81.98, 79.54, 43.19, 23.20. Anal. Calcdfor C₉H₁₁N₃: C, 67.04; H, 6.88; N, 26.07. Found: C, 67.38; H, 6.88; N,26.32.

Example 8 2-iso-Propylamino-4-[4-fluoro-phenylethynyl]pyrimidine

The title compound was prepared according to the methods described forExample 4 (89% yield). TLC: R_(f)=0.19. mp 128-129° C. IR: 3260 (br w),2970 (s), 2216 (w), 1564 (s). ¹H NMR: 8.28 (d, J=4.6 Hz, 1H), 7.60-7.50(m, 2H), 7.10-7.00 (m, 2H), 6.66 (d, J=4.9 Hz, 1H), 5.05 (d, J=7.4 Hz,1H), 4.17 (sept, J=6.5 Hz, 1H), 1.24 (d, J=6.5 Hz, 6H). ¹³C NMR: 164.23,(162.23, 161.71), 158.27, 151.24, (134.39, 134.32), (117.76, 117.74),(115.96, 115.78), 112.62, 90.37, 87.18, 42.84, 22.89. Anal. Calcd forC₁₅H₁₄FN₃: C, 70.57; H, 5.53; N, 16.46. Found: C, 70.60; H, 5.42; N,16.45.

Example 91-(2-iso-Propylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dione

The title compound was prepared according to the methods described inExample 5 (90% yield). TLC: R_(f)=0.14. mp 75-77° C. IR: 3275 (br, w),2971 (w), 1710 (m), 1682 (m). ¹H NMR (90% purity): 8.57 (s, 1H),8.00-7.90 (m, 2H), 7.23-7.15 (m, 3H), 5.08 (s, 1H), 3.73 (br s, 1H),1.09 (s, 6H). Anal. Calcd for C₁₅H₁₄FN₃O₂: C, 62.71; H, 4.91; N, 14.63;Found: C, 62.90; H, 4.84; N, 14.76.

Example 10tert-Butyl-{4-[5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyrimidin-2-yl}-amine

A mixture of1-(2-iso-propylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dione(12.5 g, 43.5 mmol), hexamethylenetetramine (12.2 g, 87.1 mmol), NH₄OAc(17 g, 220 mmol), and Na₂SO₄ (12 g) in AcOH (150 mL) was heated at 65°C. After 4 h, the mixture was cooled to rt. The mixture was filtered,washing with AcOH. The filtrate was concentrated, and the residue wasdissolved in CH₂Cl₂. The organic solution was washed with 1 N NaOH,dried (Na₂SO₄), and concentrated. The crude product was purified bycolumn chromatography (MeOH/hexanes) to afford the title compound as alight yellow solid (6.8 g, 52%). TLC (10% MeOH/CH₂Cl₂): R_(f)=0.21. ¹HNMR: 8.13 (br s, 1H), 7.84 (br s, 1H), 7.61 (br s, 2H), 7.14 (t, J=7.8Hz, 2H), 6.87 (br s, 1H), 5.31 (br s, 1H), 4.14 (br s, 1H), 1.26 (d,J=9.8 Hz, 6H). HRMS (ESI): [M+H]⁺ calcd. for C₁₆H₁₇FN₅, 298.1463; found,298.1461.

Example 11tert-Butyl-{4-[5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyrimidin-2-yl}-amine

The title compound was prepared from1-(2-tert-butylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dioneaccording to the methods described in Example 10 (56%). TLC (10%MeOH/CH₂Cl₂): R_(f)=0.22. ¹H NMR: 8.04 (d, J=5.3 Hz, 1H), 7.75 (br s,1H), 7.56 (dd, J=8.5, 5.5 Hz, 2H), 7.12 (t, J=8.6 Hz, 2H), 6.63 (d,J=5.3 Hz, 1H), 5.76 (br s, 1H), 1.45 (s, 9H). ¹³C NMR: 163.75, (161.78,161.47), 157.33, 156.21, 140.42, 135.61, (130.97, 130.90), (130.07,130.05), 126.13, (115.63, 115.46), 105.31, 50.86, 28.98. HRMS (ESI):[M+H]⁺ calcd. for C₁₇H₁₉FN₅, 312.1619; found, 312.1631.

Example 12{4-[2-(4-Chloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyrimidin-2-yl}-isopropyl-amine

The title compound was prepared from1-(2-iso-propylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dione,4-chlorobenzaldehyde, and NH₄OAc according to the methods described inExample 10 (62%). The reaction time was 48 h. TLC (50% EtOAc/hexanes):R_(f)=0.44. ¹H NMR: 10.52 (br s, 1H), 8.11 (d, J=5.2 Hz, 1H), 7.87 (d,J=8.5 Hz, 2H), 7.61 (dd, J=7.6, 5.8 Hz, 2H), 7.42 (d, J=8.5 Hz, 2H),7.13 (d, J=8.5 Hz, 2H), 6.61 (br s, 1H), 5.22 (br s, 1H), 4.17 (br s,1H), 1.25 (br s, 6H). ¹³C NMR: 163.86, 161.88, 161.41, 158.06, 145.59,135.41, (131.08, 131.02), 129.17, 126.84, (115.63, 115.46), 105.59,42.83, 22.89 (weak signals for some carbon members). HRMS (ESI): [M+H]⁺calcd. for C₂₂H₂₀ClFN₅, 408.1386; found, 408.1404.

Example 13tert-Butyl-{4-[2-(4-chloro-phenyl)-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyrimidin-2-yl}-amine

The title compound was prepared from 1-(2-tert-butylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)ethane-1,2-dione, 4-chlorobenzaldehyde, and NH₄OAcaccording to the methods described in Example 12 (68%). TLC (50%EtOAc/hexanes): R_(f)=0.60. ¹H NMR: 10.52 (br s, 1H), 8.10 (d, J=4.7 Hz,1H), 7.82 (d, J=8.5 Hz, 2H), 7.65 (br s, 2H), 7.40 (d, J=8.3 Hz, 2H),7.12 (br s, 2H), 6.58 (br s, 1H), 5.29 (br s, 1H), 1.49 (s, 9H). ¹³CNMR: 163.79, (161.82, 161.77), 157.86, 145.48, 135.32, (130.99, 130.93),129.15, 127.68, 126.71, (115.63, 115.45), 105.32, 50.86, 29.02 (weaksignals for some carbon members). HRMS (ESI): [M+H]⁺ calcd. forC₂₃H₂₂ClFN₅, 422.1542; found, 422.1563.

Example 14tert-Butyl-{4-[2-dimethoxymethyl-5-(4-fluoro-phenyl)-1H-imidazol-4-yl]-pyrimidin-2-yl}-amine

The title compound was prepared from1-(2-tert-butylamino-pyrimidin-4-yl)-2-(4-fluoro-phenyl)-ethane-1,2-dione,glyoxal 1,1-dimethylacetal, and NH₄OAc, using tert-butyl methyl ether asthe solvent, according to the methods described in Example 10 (20%). Thereaction time was 48 h at rt. TLC (50% EtOAc/hexanes): R_(f)=0.19. ¹HNMR (CDCl₃): 10.29 (br s, 1H), 8.07 (d, J=5.2 Hz, 1H), 7.60 (dd, J=8.0,5.6 Hz, 2H), 7.11 (t, J=8.6 Hz, 2H), 6.57 (d, J=5.2 Hz, 1H), 5.55 (s,1H), 5.23 (br s, 1H), 3.46 (s, 6H), 1.49 (s, 9H). ¹³C NMR (CDCl₃):163.73, (161.87, 161.76), 157.88, 155.38, 145.20, 142.04, (131.03,130.97), 130.69, 124.84, (115.50, 115.33), 105.33, 98.08, 53.60, 50.87,29.04. MS (ESI): [M+H]⁺ calcd. for C₂₀H₂₄FN₅O₂, 385.19; found, 386.1.

Example 15 2-Chloro-4-(4-fluoro-phenylethynyl)-pyrimidine

The title compound was prepared from 2,4-dichloropyrmidine and1-ethynyl-4-fluorobenzene using methods analogous to those described inExample 2 (65%). TLC (25% EtOAc/hexanes): R_(f)=0.21. mp 125-126° C. IR:3049 (w), 2210 (w), 1559 (s). ¹H NMR (CDCl₃): 8.61 (d, J=5.0 Hz, 1H),7.70-7.60 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 7.13-7.06 (m, 2H). ¹³C NMR(CDCl₃): 163.99 (d, J_(C-F)=252 Hz), 161.86, 159.66, 153.39, 134.96 (d,J_(C-F)=8.6 Hz), 121.77, 116.96 (d, JC-F=3.4 Hz), 116.40 (d, J_(C-F)=22Hz), 95.27, 85.89. Anal. Calcd for C₁₂H₆ClFN₂: C, 61.95; H, 2.60; N,12.04; Found: C, 62.15; H, 2.83; N, 12.00.

Example 16 Alternative preparation for2-iso-Propylamino-4-[4-fluoro-phenylethynyl]pyrimidine

A solution of 2-chloro-4-(4-fluoro-phenylethynyl)-pyrimidine (1 equiv.)in iso-propylamine (0.2 M) is heated at 35° C. for 24 h. The mixture iscooled to rt, diluted with water, and extracted with EtOAc. The organiclayer is concentrated and the residue purified by column chromatographyto provide the title compound.

Example 17 Alternative preparation for2-tert-Butylamino-4-[4-fluoro-phenylethynyl]pyrimidine

A solution of 2-chloro-4-(4-fluoro-phenylethynyl)-pyrimidine (1 equiv.)in tert-butylamine (0.2 M) is heated at 80° C. in a sealed tube for 24h. The mixture is cooled to rt, diluted with water, and extracted withEtOAc. The organic layer is concentrated and the residue purified bycolumn chromatography to provide the title compound.

The compounds in Examples 18-21 may be prepared using the methodsdescribed in the preceding examples.

Example 18(R)-(1-Phenyl-ethyl)-[4-(3-trifluoromethyl-phenylethynyl)-pyrimidin-2-yl]-amine

Example 19(R)-1-[2-(1-Phenyl-ethylamino)-pyrimidin-4-yl]-2-(3-trifluoromethyl-phenyl)-ethane-1,2-dione

Example 20(R)-4-[5-[2-(1-Phenyl-ethylamino)-pyrimidin-4-yl]-4-(3-trifluoromethyl-phenyl)-1H-imidazol-2-yl]-piperidine-1-carboxylicacid tert-butyl ester

Deprotection and alkylation methods known in the art may be used toconvert Example 20 into compound 2.

1. A method of making imidazoles of Formula (III):

wherein R¹ and R² are each independently selected from the groupconsisting of —H, —C₁₋₆alkyl, —C₃₋₈cycloalkyl, benzyl, and1-methylbenzyl; x is 0, 1, 2, or 3; each R³ is independently selectedfrom the group consisting of —OH, —Cl, —F, —C₁₋₆alkyl, —C₃₋₈cycloalkyl,—OC₁₋₆alkyl, —CF₃, —OCF₃, phenyl, —CN, —NO₂, —N(R^(a))R^(b),—C(O)N(R^(a))R^(b), —N(R^(c))C(O)R^(d), —N(R^(c))SO₂C₁₋₆alkyl,—C(O)C₁₋₆alkyl, —S(O)₀₋₂C₁₋₆alkyl, —SO₂N(R^(a))R^(b), —CO₂H, and—CO₂C₁₋₆alkyl, where R^(a) and R^(b) are each independently —H or—C₁₋₆alkyl, and where R^(c) and R^(d) are each independently —H or—C₁₋₆alkyl; and R⁴ is —H, —C₁₋₈alkyl, —C₃₋₈cycloalkyl, aryl, heteroaryl,heterocycloalkyl, or —CH(OC₁₋₆alkyl)₂; or tautomers, enantiomers,diastereomers, or pharmaceutically acceptable salts or esters thereof;comprising: oxidizing an alkyne of Formula (II):

with finely powdered potassium permanganate, wherein R¹, R², R³, and xare defined as in compound of Formula (III).
 2. A method as recited inclaim 1, wherein said oxidizing is performed in a buffered acetone/H₂Osolution.
 3. A method as recited in claim 1, wherein said oxidizing saidalkyne of Formula (II) generates a 1,2-diketone of Formula (I):

and further comprising reacting said 1,2-diketone of Formula (I) with atleast one of R⁴CHO and a formaldehyde equivalent to generate a compoundof Formula (III).
 4. A method as recited in claim 3, wherein saidreacting is performed in the presence of an ammonia equivalent.
 5. Amethod as recited in claim 4, wherein said ammonia equivalent isselected form the group consisting of ammonia, ammonium acetate, andmixtures thereof.
 6. A method as recited in claim 3, wherein saidformaldehyde equivalent is selected form the group consisting ofhexamethylenetetramine, formaldehyde, and mixtures thereof.
 7. A methodas recited in claim 1, wherein said compound of Formula (III) iscompound of Formula (III′):

or a tautomer thereof, and said compound of Formula (II) is compound ofFormula (II′):

wherein R^(2′) is isopropyl or t-butyl, and R^(4′) is H, 4-chlorophenyl,or —CH(OCH₃)₂.
 8. A method as recited in claim 1, further comprising:reacting 2,4-dichloropyrimidine with a compound of Formula (VII):

to form a compound of Formula (VIII):


9. A method as recited in claim 1, further comprising: reacting acompound of Formula (VIII):

with R¹R²NH to form a compound of Formula (II):


10. A method as recited in claim 1, further comprising: reacting2,4-dichloropyrimidine with a compound of Formula (VII):

to form a compound of Formula (VIII):

and reacting a compound of Formula (VIII) with R¹R²NH to form a compoundof Formula (II):


11. A method as recited in claim 1, wherein a compound of Formula (II)is a compound of Formula (II′):

and a compound of Formula (III) is a compound of Formula (III′):

wherein R^(2′) is isopropyl or t-butyl and R^(4′) is —H, 4-chlorophenyl,or —CH(OCH₃)₂.
 12. A method as recited in claim 11, further comprising:reacting 2,4-dichloropyrimidine with 1-ethynyl-4-fluorobenzene to form acompound of formula (VIII′):


13. A method as recited in claim 11, further comprising: reacting acompound of formula (VIII′) with R^(2′)NH to form a compound of Formula(II′).
 14. A method as recited in claim 11, further comprising: reacting2,4-dichloropyrimidine with 1-ethynyl-4-fluorobenzene to form a compoundof formula (VIII′):

and reacting a compound of formula (VIII′) with R^(2′)NH to form acompound of Formula (II′).